Pharmaceutical solids can exist in different crystal forms, such as crystalline, amorphous, or glass and also in solvated or hydrated states (Haleblian et al., 1969, 1975; Kuhnert-Brandstaetter, 1973; Sohn 2004). Polymorphism is the ability of any element or compound to crystallize as more than one distinct crystal species.
It is a well known fact that different polymorphic forms of the same drug may have substantial differences in certain pharmaceutically-important physicochemical properties, such as stability, solubility, dissolution rate, crystal habit, tableting behavior. Changes in certain of these physiochemical properties may ultimately affect the bioavailability of the drug. Furthermore, different physical forms may have different particle size, hardness and glass transition temperatures.
Regulatory authorities desire to have all possible polymorphic forms of a new drug substance identified prior to approval of a product containing the drug. However, as is well known in the art, the existence of polymorphic forms of any given compound cannot be predicted, and there is no standard procedure for proceeding to make a previously unknown polymorphic form. Even after a polymorph has been identified, there is no possibility of predicting whether any additional forms will ever be discovered. This has been described in many recent articles, including A. Goho, Science News, Vol. 166, No. 8, pages 122-123 (August 2004).
Doxazosin mesyalte is a quinazoline compound, that is a selective inhibitor of the α-1 subtype of α-adrenergic receptors. It is known to be useful in men to treat the symptoms of an enlarged prostate (benign prostatic hyperplasia or BPH), which include difficulty urinating (hesitation, dribbling, weak stream, and incomplete bladder emptying), painful urination, and urinary frequency and urgency. Doxazosin (Cardura) is also used alone or in combination with other medications to treat high blood pressure. Doxazosin is in a class of medications called alpha-blockers. It relieves the symptoms of BPH by relaxing the muscles of the bladder and prostate. It lowers blood pressure by relaxing the blood vessels so that blood can flow more easily through the body.
Literature data show that the doxazosin mesylate exists in different crystalline polymorphic forms.
The Chinese Journal of Medicinal Chemistry (1995, 5:266-270) described for the first time three crystal forms: Form A, Form B and Form C.
Subsequently, M. Greman et al. (Farmacevtski vestnik, 1997, 48: 292-293) described five different forms, namely A, B, C, D, and E of doxazosin mesylate.
Grafe and Morsdorf (CA 02224884, CA 0224916, CA 0222022) disclose methods of preparation of doxazosin mesylate forms which do not correspond to the polymorphic form of the present invention.
WO99/35143 and WO00/56731 claim processes for preparing Form A.
US 2002/0065287 A1 (Giridher et al.) describes two crystal forms A and D.
EP 849264, EP 849265 and EP 849266 disclose three crystalline forms of doxazosin mesylate Form I, Form II and Form III respectively.
Young-Taek Soh and Yoon-Hee Lee in Arch Pharm Res Journal (Vol 28, No. 6. 730-735, 2005) have recently described nine forms of doxazosin mesylate. The XRD patterns of nine doxazosin mesyalte forms are different from those previously reported in the literature.
Consequently, it would be a significant contribution to the art to provide a crystalline form of doxazosin mesylate, having increased solubility, and methods of preparation, pharmaceutical formulations, and methods of use thereof.